As I just mentioned I received another thoughtful comment from Reese Clark, which I reproduce in its entirety below:

“After re-reading my post and at the risk of being a bit redundant with what Dr Barrington has already carefully presented – I offer a bit more thoughtful comment

Oxygen is a toxic drug and it should be used and monitored with great caution.1-6

Results of clinical trials are always important and they offer important information. The interpretation of the results can be wrong.

Narrowing oxygen targets/limits increases the frequency of alarms and we begin to ignore alarms (especially the high alarms), and that is a mistake.

We manage the high end; the baby more often determines the low end. We can make a baby have a 100% oxygen saturation. Providing oxygen treatment to an infant who is not breathing will not make their oxygen saturation better.

Our “therapeutic response” to pulse oximeter alarms is likely to be more important than the limits/targets themselves.

We may have studied the wrong thing in the wrong way. Schmidt et al7 showed “Caregivers maintained saturations at lower displayed values in the higher than in the lower target group. This differential management reduced the separation between the median true saturations in the 2 groups by approximately 3.5%”. Thus “the design of the oximeter masking algorithm may have contributed to the smaller-than-expected separation between true saturations …” If the differences in the two study groups is small, how can we attribute any outcome to one group or the other.

The mortality finding is small and confounded by site of care and revision of the pulse oximeter algorithm. To reproduce the results in another prospective study would be hard. Site variation in mortality is greater than the mortality findings in any of the pulse oximeter studies.8, 9

We need to see outcomes by site in order to understand the overall results. What if one or two sites drove the overall findings? For sure we can say New Zealand reports different results from the UK.

A total of 2448 infants were enrolled in the three trials (973 in the United Kingdom, 1135 in Australia, and 340 in New Zealand). In combined data, there was no significant difference in rate of death in the lower-target group, as compared with the higher-target group (19.2% vs. 16.6%; relative risk, 1.16, 95% CI, 0.98 to 1.37; P = 0.09). Note that the mortality in the NZ cohort was lower and in the opposite direction of the combined data.10

We now have 2 year follow-up data. Data from New Zealand11 follow up at 2 years shows death or major disability at 2 years’ is lower in the low oxygen group compared to the high oxygen group (Death or major disability 65/167 (38.9) in the lower target group; 76/168 (45.2) in the higher target group). The relative risk of a bad outcome was higher in the high oxygen group RR=1.15 (0.90-1.47); p=0.26. Death occurred in 25 (14.7%) and 27 (15.9%) of those randomized to the lower and higher target, respectively, and blindness in 0% and 0.7%. These data do not support the concept that high oxygen saturations promote better outcomes or that low oxygen targets promote worse outcomes.

But now, the data from the UK and Australia are reported and show use of an oxygen-saturation target range of 85 to 89% versus 91 to 95% resulted in nonsignificantly higher rates of death or disability at 2 years in each trial, but significantly increased risks of this combined outcome and of death alone in post hoc combined analyses.12 In post hoc combined, unadjusted analyses that included all oximeters, death or disability occurred in 492 of 1022 infants (48.1%) in the lower-target group versus 437 of 1013 infants (43.1%) in the higher-target group (relative risk, 1.11; 95% CI, 1.01 to 1.23; P=0.02). Death occurred in 222 of 1045 infants (21.2%) in the lower-target group versus 185 of 1045 infants (17.7%) in the higher-target group (relative risk, 1.20; 95% CI, 1.01 to 1.43; P=0.04).” Note the mortality rates are higher here than reported in the NZ data.

Again, where a premature infant is born is as important as any specific therapy that you receive.13-15

Carlo et al16 astutely pointed out that during the SUPPORT trial “The infants in both treatment groups had lower rates of death before discharge (16.2% in the higher-oxygen-saturation group and 19.9% in the lower-oxygen-saturation group), than did those who were not enrolled (24.1%) and historical controls (23.1%), and rates of blindness (even though severe ROP decreased) did not differ between the treatment groups.” Therefore, being in the study and in the lower-oxygen-saturation group was associated with improved outcomes (4.2 percent less mortality in patients in the lower-oxygen-saturation group to non-enrolled patients. There was only a 3.7% between group difference in SUPPORT study patients)

STOP ROP – Use of supplemental oxygen at pulse oximetry saturations of 96% to 99% did not cause additional progression of pre-threshold ROP, but also did not significantly reduce the number of infants requiring peripheral ablative surgery. A subgroup analysis suggested a benefit of supplemental oxygen among infants who have pre-threshold ROP without plus disease, however, this finding requires additional study. Supplemental oxygen increased the risk of adverse pulmonary events, including pneumonia and/or exacerbations of chronic lung disease and the need for oxygen, diuretics, and hospitalization at 3 months of corrected age.17